Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale.
|Title||Conformational dynamics of the human propeller telomeric DNA quadruplex on a microsecond time scale.|
|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Islam, Barira, Sgobba Miriam, Laughton Charlie, Orozco Modesto, Sponer Jiri, Neidle Stephen, and Haider Shozeb|
|Journal||Nucleic Acids Res|
|Date Published||2013 Feb 1|
|Keywords||Cluster Analysis, DNA, G-Quadruplexes, Humans, Molecular Dynamics Simulation, Potassium, Telomere, Water|
The human telomeric DNA sequence with four repeats can fold into a parallel-stranded propeller-type topology. NMR structures solved under molecular crowding experiments correlate with the crystal structures found with crystal-packing interactions that are effectively equivalent to molecular crowding. This topology has been used for rationalization of ligand design and occurs experimentally in a number of complexes with a diversity of ligands, at least in the crystalline state. Although G-quartet stems have been well characterized, the interactions of the TTA loop with the G-quartets are much less defined. To better understand the conformational variability and structural dynamics of the propeller-type topology, we performed molecular dynamics simulations in explicit solvent up to 1.5 μs. The analysis provides a detailed atomistic account of the dynamic nature of the TTA loops highlighting their interactions with the G-quartets including formation of an A:A base pair, triad, pentad and hexad. The results present a threshold in quadruplex simulations, with regards to understanding the flexible nature of the sugar-phosphate backbone in formation of unusual architecture within the topology. Furthermore, this study stresses the importance of simulation time in sampling conformational space for this topology.